Because sexual transmission of HIV occurs across mucosal membranes, understanding the immune responses of the genital mucosa to vaccines may contribute knowledge to finding an effective candidate HIV vaccine. We describe the uptake of rectal secretion, cervical secretion and seminal mucosal secretion sampling amongst volunteers in a Phase 1b HIV vaccine trial. Age at screening, gender, study site and the designation of the person conducting the informed consent procedure were collected for volunteers who screened for the HVTN 097 study. A total of 211 volunteers (54% female) were screened at three sites in South Africa: Soweto (n = 70, 33%), Cape Town (n = 68, 32%) and Klerksdorp (n = 73, 35%). Overall uptake of optional mucosal sampling amongst trial volunteers was 71% (n = 149). Compared to Cape Town, volunteers from Soweto and Klerksdorp were less likely to consent to sampling (Soweto OR 0.08 CI: 0.03–0.25 p<0.001 and Klerksdorp OR 0.13 CI: 0.04–0.41 p = 0.001). In contrast, volunteers over 25 years of age were 2.39 times more likely to consent than younger volunteers (CI: 1.13–5.08, p = 0.02). Further studies are required to better understand the cultural, demographic and sociobehavioral factors which influence willingness to participate in mucosal sampling in HIV prevention studies.

Methods. Within a randomized trial of daily acyclovir 400 mg twice daily in African HIV-1 serodiscordant couples, in which the HIV-1–infected partner was HSV-2 seropositive, we identified partnerships in which HIV-1–susceptible partners were HSV-2 seronegative to estimate the effect of acyclovir on risk of HSV-2 transmission.

The epidemiology and impact of multiple concurrent Human papillomavirus (HPV) infections on the natural history of cervical disease is uncertain, but could have significant implications for cervical cancer prevention and HPV vaccination strategies.

Methods

A cross-sectional prevalence study was conducted to determine the overall prevalence of HPV and the rate of multiple concurrent HPV infections, in a cohort of sexually active HIV-uninfected South African adolescents. HPV genotyping was performed using the polymerase chain reaction.

Results

Overall prevalence of HPV was 64.1%. Multiple concurrent HPV infections were found in 43.6% of participants and 68% of HPV-infected participants. Non-vaccine high-risk HPV (HR-HPV) genotypes were found much more often than vaccine types (HPV16 and HPV18).

Conclusions

Our cohort of young South African females was found to have a high overall prevalence of HPV and multiple concurrent HPV infections. Most HR-HPV infections found were genotypes other than HPV16 or HPV18.

Forty-eight communities were enrolled at five sites in South Africa, Tanzania, Zimbabwe, and Thailand. CBVCT was designed to make testing more accessible in communities, engage communities through outreach, and provide post-test support services. SVCT comprised standard VCT services established at existing facilities. Communities were randomized in matched pairs to 36 months of CBVCT or SVCT. Data were collected at baseline (n=14,567) and post-intervention (n=56,683) by cross-sectional random surveys of 18–32 year-old community residents. HIV incidence was estimated using a cross-sectional multi-assay algorithm. Thailand was excluded from incidence analyses due to low HIV prevalence.

Findings

The estimated incidence in the CBVCT was 1.52% vs. 1.81% in the SVCT with an estimated reduction in HIV incidence of 13·9% (relative risk [RR]=0·86; 95% confidence interval [CI]=0·725–1·023; p=0·08). Women older than 24 years had RR=0·70 (95% CI=0·54–0·90; p=0·009). CBVCT increased testing rates by 25% overall (95% CI=12%–39%; p=0·0003), by 45% among men and 15% among women. No overall effect on sexual risk behaviour was observed. However, among HIV-infected participants, CBVCT reduced the number of sexual partners by 8% (95% CI=1%–15%; p=0.03) and the proportion of multiple partnerships by 30% (95% CI=8%-46%; p=0.01). Social norms regarding HIV testing were improved in CBVCT communities.

Interpretations

The intervention was effective in increasing HIV testing, particularly among men, promoted positive social norms regarding testing, and reduced behavioural risk among HIV-infected participants. A modest reduction in HIV incidence was observed. This intervention focused primarily on HIV detection. Current and future studies that include strategies for HIV treatment and viral suppression should demonstrate further incidence reductions.

There is increased focus on HIV prevention with African men who report experiencing childhood sexual (CSA) or physical abuse (CPA).

Objective

To better understand the effects of a community-based intervention (Project Accept HPTN 043) on HIV prevention behaviors among men who report CSA or CPA experiences.

Methods

Project Accept compared a community-based voluntary mobile counseling and testing (CBVCT) intervention with standard VCT. The intervention employed individual HIV risk reduction planning with motivational interviewing in 34 African communities (16 communities at 2 sites in South Africa, 10 in Tanzania, and 8 in Zimbabwe). Communities were randomized unblinded in matched pairs to CBVCT or SVCT, delivered over 36 months. The post-intervention assessment was conducted using a single, cross-sectional random survey of 18-32 year-old community members (total N = 43,292). We analyzed the effect of the intervention on men with reported CSA or CPA across the African sites. Men were identified with a survey question asking about having experienced CSA or CPA across the lifespan. The effect of intervention on considered outcomes of the preventive behavior was statistically evaluated using the logistic regression models.

Results

Across the sites, the rates of CSA or CPA among men indicated that African men reflected the global prevalence (20%) with a range of 13–24%. The statistically significant effect of the intervention among these men was seen in their increased effort to receive their HIV test results (OR 2.71; CI: (1.08, 6.82); P: 0.034). The intervention effect on the other designated HIV prevention behaviors was less pronounced.

Conclusion

The effect of the intervention on these men showed increased motivation to receive their HIV test results. However, more research is needed to understand the effects of community-based interventions on this group, and such interventions need to integrate other keys predictors of HIV including trauma, coping strategies, and intimate partner violence.

Background. Despite high herpes simplex virus type 2 (HSV-2) incidence and prevalence among women in Africa, we are unaware of published neonatal herpes reports. To assess neonatal HSV transmission potential in South Africa, we investigated the frequency of the strongest risk factors: HSV acquisition in late pregnancy and HSV shedding during labor. Methods. Women admitted in early labor to a hospital in Soweto underwent HSV serologic testing and genital swab collection for HSV PCR. HSV-2 seronegative women were assessed for seroconversion 4–6 weeks after delivery. Results. Of 390 women enrolled, 229 (58.7%) were HSV-2 seropositive. Genital HSV-2 was detected in 17.2% of HSV-2 seropositive women, including 26 of 115 HIV-positive and 13 of 110 HIV-negative women (22.6% versus 11.8%; RR, 1.91; 95% CI, 1.04–3.53; P = 0.038), but in none of 161 HSV-2 seronegative women. Among the 91 HSV-2 seronegative women followed after delivery, none seroconverted. Conclusions. HSV-2 reactivation is common among South African women during labor, especially those with HIV coinfection. To determine the epidemiology of neonatal herpes in South Africa and to investigate whether the lack of reported cases is due to alterations in immune control or HSV-2 virulence, studies evaluating acutely ill neonates for HSV and studies of maternal HSV-2 shedding patterns are needed.

CD4 count is a proxy for the extent of immune deficiency and declines in CD4 count are a measure of disease progression. Decline in CD4 count is an important component: for estimating benefits of ARV treatment; for individual level counselling on the rapidity of untreated disease progression and prognosis; and can be used in planning demand for health services. Our objective is to report CD4 decline and changes in viral load (VL) in a group of HIV-infected adults enrolled in a randomized trial of preventive treatment for TB in South Africa where clade C infection predominates.

Methods

HIV-infected, tuberculin skin test positive adults who were not eligible for antiretroviral (ARV) treatment were randomized to a trial of preventive treatment from 2003–2005. VL and CD4 count were assessed at enrollment and CD4 counts repeated at least annually. During follow-up, individuals whose CD4 counts decreased to <200 cells/mm3 were referred for antiretroviral therapy (ART) and were analytically censored.

Recent data suggest that infection with human immunodeficiency virus type 1 (HIV-1) subtype C results in prolonged high-level viremia (>5 log10 copies/mL) during early infection. We examined the relationship between HIV-1 subtype and plasma viremia among 153 African seroconverters. Mean setpoint viral loads were similar for C and non-C subtypes: 4.36 vs 4.42 log10 copies/mL (P = .61). The proportion of subtype C–infected participants with viral loads >5 log10 copies/mL was not greater than the proportion for those with non-C infection. Our data do not support the hypothesis that higher early viral load accounts for the rapid spread of HIV-1 subtype C in southern Africa.

By comparing younger to older participants enrolled in a HIV vaccine efficacy trial, we aimed to gain insights into the inclusion of adolescents in future trials. This was a sub-analysis of a multisite HIV vaccine randomized clinical trial in South Africa, conducted January-September, 2007. Motivations for trial enrollment, social harms, adverse events, and loss to follow-up were compared between younger (18-20 years old) and older participants (21-35 years old). Both younger (n=238) and older participants (n=563) were equally likely to report enrolling for altruistic reasons. Younger females were less likely than older participants to join for trial reimbursement (p=0.005), while younger males were more likely to enroll because the vaccine may provide protection from HIV-acquisition (p<0.001). There were no significant differences in the number of social harms reported. Compared to males over 20 years-old, 18-20-year-old females were less likely to experience adverse events (OR=0.1, CI 0.01-0.80) and no more likely to be lost to follow up (OR=0.7, CI 0.39-1.25), while 18-20-year-old males were no more likely to experience adverse events (OR=1.3, CI 0.58-2.83) or loss to follow-up (OR=0.8, CI 0.51-1.41). Our data support the inclusion of younger participants who are at risk for HIV in future HIV vaccine efficacy trials.

A large proportion of HIV infected adults not qualifying for immediate ART at the CD4 count threshold of 350 cells/mm3 have high viral loads. HIV-infected men at their first HIV diagnosis are more likely to have lower CD4 counts and higher viral loads than women.

Self-sampling for Human Papillomavirus (HPV) testing may offer improved patient acceptability, decreased cost, and greater practicality than clinician collection of specimens. HPV testing among adolescents is necessary to conduct vaccine surveillance and may play a role in cervical cancer screening among some populations.

Methods

A cross-sectional prevalence study was conducted to compare the results of self-collected and clinician-collected specimens for Human papillomavirus (HPV) testing among South African adolescent females. All participants provided self-sampled vaginal swabs and underwent clinician-collection of cervical swabs for HPV DNA analysis. The level of agreement between HPV DNA results from the two specimen collection methods was measured.

Results

The level of agreement between HPV DNA results from self-collected and clinician-collected specimens was high (κ=86.7; p<0.001). A high prevalence of HPV overall was found by both specimen collection methods (57%; 95% CI 0.37–0.75). Low-risk HPV (LR-HPV) types were found slightly more frequently in self-collected specimens.

Conclusion

There is a high level of agreement between the HPV DNA results from self-collected and clinician-collected specimens. Self-collection of specimens for HPV testing is a viable alternative among adolescents.

We hypothesize that time to initiate care and maturity of a treatment program impact on outcome of severely immuno-compromised patients with higher risk of mortality.

Design

We conducted a retrospective cohort analysis at the Perinatal HIV Research Unit Adult ART clinic, Soweto, South Africa.

Methods

Eligibility criteria for this analysis were: attendance for minimum one visit between August 2004 and August 2010, age >18 years, CD4 count < 50 cells/mm3 and ART-naïve at screening. We followed participants up to one year after ART initiation. We defined years 2004-2007 and 2008-2010 as the early and late eras respectively. Chi-square test and survival analysis methods were used for mortality comparisons between eras.

Results

Of 2357 patients eligible for antiretroviral treatment, 395 (17%) had CD4 counts < 50 cells/mm3 and ART-naïve at screening. Overall 261 (66%) were women. Patients had similar median age (35 vs. 33.5 years, p=0.08), time to HAART initiation (7 days, p=0.18) and baseline CD4 count (20 vs. 23 cells/mm3, p=0.5) between eras. Overall 63 (16%) patients died in their first year of treatment (2 per 100 person-months) and the main cause of death was tuberculosis (n=23, 37%). The proportion of deaths (52/262 vs. 11/133, p=0.003) and time to death from enrolment (logrank p=0.04) were significantly different between eras.

Conclusion

Mortality decreased as the ART program matured in Soweto while time to initiation of treatment remained similar in both eras. Because ART guidelines were consistent during both eras, it is possible that with time, management of patients improved as expertise was gained.

Recent studies have reported that founder viruses play unique roles in establishing HIV-1 infection. Understanding the biological and immunological features of envelope glycoproteins (Env) from such viruses may facilitate the development of effective vaccines against HIV-1. In this report, we evaluated the immunogenicity of gp120 immunogens from two pairs of clade B and two pairs of clade C mother-to-child transmitted (MTCT) HIV-1 variants that had various levels of sensitivity to broadly neutralizing monoclonal antibodies. Individual gp120 DNA and protein vaccines were produced from each of the eight MTCT Env antigens included in the current study. Rabbits were immunized with these gp120 immunogens by the DNA prime-protein boost approach. High level Env-specific antibody responses were elicited by all MTCT gp120 immunogens. However, their abilities to elicit neutralizing antibody (NAb) responses differed and those from relatively neutralization-resistant variants tended to be more effective in eliciting broader NAb. Results of this pilot study indicated that not all MTCT Env proteins have the same potential to elicit NAb. Understanding the mechanism(s) behind such variation may provide useful information in formulating the next generation of HIV vaccines.

With the rollout of antiretroviral therapy in South Africa and its potential to prolong the lives of HIV-infected individuals, understanding the sexual behavior of HIV-positive people is essential to curbing secondary HIV transmission.

Methods

We surveyed 3819 HIV-positive patients during their first visit to an urban wellness clinic and a rural wellness clinic.

Results

Urban residents were more likely than rural residents to have current regular sex partners (75.1% vs. 46.0%; χ2 odds ratio [OR] = 3.531; P < 0.001), to have any current sexual partners (75.3% vs. 51.2%; χ2 OR = 2.908; P < 0.001), and to report consistent condom use with regular partners (78.4% vs. 48.3%; χ2 OR = 3.886; P < 0.001) and with casual partners (68.6% vs. 48.3%; χ2 OR = 2.337; P < 0.001). In multivariate analysis, independent predictors of consistent condom use with regular partners included across gender, urban residence, and higher education levels; for women, disclosure and younger age; and for men only, no history of alcohol consumption. Male and female participants with a casual sexual partner were less likely to use a condom consistently with regular partners. Additionally, urban residence and a CD4 count greater than 200 cells/mm3 as well as (for women only) a higher household income and a history of alcohol consumption were predictors of having a regular sexual partner.

Conclusions

HIV prevention programs in South Africa that emphasize the importance of condom use and disclosure and are tailored to the needs of their attending populations are critical given the potential for HIV-infected individuals to resume risky sexual behavior with improving health.

We assessed prevalence and factors associated with hepatitis B in a cross-section of HIV-infected primary care and anti-natal clinic patients in South Africa and evaluated a rapid hepatitis B surface antigen (HBsAg) assay. We enrolled 998 patients; 88% were women, median age was 29 years, and median CD4 count was 354 cells/mm3. HBsAg ELISA, anti-hepatitis B core (HBc) antibodies, and hepatitis C virus antibody were positive among 4.2%, 37%, and 0.1% of subjects, respectively. Univariate and multivariate associations were assessed using logistic regression. Anti-HBc antibodies were associated with alcohol use, traditional medicines, and higher CD4. HBsAg positivity was associated with lower CD4. Compared to the HBsAg ELISA, a rapid HBsAg test had a sensitivity of 75.0% and specificity of 99.6%. In conclusion, we identified a moderate prevalence of both HBsAg and anti-HBc. Importantly, we found subjects with HBsAg positivity had lower CD4 counts.

In South Africa, the prevalence of oncogenic Human Papillomavirus (HPV) may be as high as 64%, and cervical cancer is the leading cause of cancer-related death among women. The development of efficacious prophylactic vaccines has provided an opportunity for primary prevention. Given the importance of psycho-social forces in vaccine uptake, we sought to elucidate factors influencing HPV vaccination among a sample of low-income South African adolescents receiving the vaccine for the first time in Soweto.

Methods

The HPV vaccine was introduced to adolescents in low-income townships throughout South Africa as part of a nationwide trial to understand adolescent involvement in future vaccine research targeting human immunodeficiency virus (HIV). We performed in-depth semi-structured interviews with purposively-sampled adolescents and their care providers to understand what forces shaped HPV vaccine uptake. Interviews were recorded, transcribed, translated, and examined using thematic analysis.

Results

Of 224 adolescents recruited, 201 initiated the vaccine; 192 (95.5%) received a second immunization; and 164 (81.6%) completed three doses. In our qualitative study of 39 adolescent-caregiver dyads, we found that factors driving vaccine uptake reflected a socio-cultural backdrop of high HIV endemnicity, sexual violence, poverty, and an abundance of female-headed households. Adolescents exercised a high level of autonomy and often initiated decision-making. Healthcare providers and peers provided support and guidance that was absent at home. The impact of the HIV epidemic on decision-making was substantial, leading participants to mistakenly conflate HPV and HIV.

Conclusions

In a setting of perceived rampant sexual violence and epidemic levels of HIV, adolescents and caregivers sought to decrease harm by seeking a vaccine targeting a sexually transmitted infection (STI). Despite careful consenting, there was confusion regarding the vaccine’s target. Future interventions promoting STI vaccines will need to provide substantial information for participants, particularly adolescents who may exercise a significant level of autonomy in decision-making.

HIV rapid tests were performed in-country. HIV status was confirmed at a central laboratory in the United States. HIV incidence was estimated using a multi-assay algorithm (MAA) that included the BED capture immunoassay, an avidity assay, CD4 cell count, and HIV viral load.

Results

Data from Thailand was not used in the endpoint analysis because HIV prevalence was low. Overall, 7,361 HIV infections were identified (4 acute, 3 early, and 7,354 established infections). Samples from established infections were analyzed using the MAA; 467 MAA positive samples were identified; 29 of those samples were excluded because they contained antiretroviral drugs. HIV prevalence was 16.5% (range at study sites: 5.93% to 30.8%). HIV incidence was 1.60% (range at study sites: 0.78% to 3.90%).

Conclusions

In this community-randomized trial, a MAA was used to estimate HIV incidence in a single, cross-sectional post-intervention survey. Results from this analysis were subsequently used to compare HIV incidence in the control and intervention communities.

Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed-uninfected infants had higher representation of WT/Hap-A1 than infected infants (excluding intrapartum-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction (P=0.04; OR=0.33). Mother-infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased intrapartum transmission: WT/Hap-A3 was increased in intrapartum vs. non-transmitting mothers, and remained significant post mNVP and MVL correction (P=0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the non-transmitting mothers (P=0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total (P=0.001) and exposed-uninfected infants (P=0.006); the effect was not additive, however having either Hap-A1 or high CCL3L CN was more significantly (P=0.0008) associated with protection from in utero infection than Hap-A1 (P=0.028) or high CCL3L CN (P=0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.

Two CCL3 haplotypes (HapA1 and Hap-A3) and two polymorphic positions shared by the haplotypes (Hap-2SNP) were investigated together with CCL3L copy number (CN), for their role in HIV-1 disease. Hap-A1 was associated with protection from in utero HIV-1 infection: exposed-uninfected infants had higher representation of WT/Hap-A1 than infected infants (excluding intrapartum-infected infants), which maintained significance post maternal Nevirapine (mNVP) and viral load (MVL) correction (P=0.04; OR=0.33). Mother-infant pair analyses showed the protective effect of Hap-A1 is dependent on its presence in the infant. Hap-A3 was associated with increased intrapartum transmission: WT/Hap-A3 was increased in intrapartum vs. non-transmitting mothers, and remained significant post mNVP and MVL correction (P=0.02; OR=3.50). This deleterious effect of Hap-A3 seemed dependent on its presence in the mother. Hap-2SNP was associated with lower CD4 count in the non-transmitting mothers (P=0.03). CCL3 Hap-A1 was associated with high CCL3L CN in total (P=0.001) and exposed-uninfected infants (P=0.006); the effect was not additive, however having either Hap-A1 or high CCL3L CN was more significantly (P=0.0008) associated with protection from in utero infection than Hap-A1 (P=0.028) or high CCL3L CN (P=0.002) alone. Linkage disequilibrium between Hap-A1 and high CCL3L CN appears unlikely given that a Nigerian population showed an opposite relationship.

Besides access to medical male circumcision, HIV testing, access to condoms and consistent condom use are additional strategies men can use to prevent HIV acquisition. We examine male behavior toward testing and condom use.

Objective

To determine factors associated with never testing for HIV and consistent condom use among men who never test in Soweto.

Methods

A cross-sectional survey in Soweto was conducted in 1539 men aged 18–32 years in 2007. Data were collected on socio-demographic and behavioral characteristics to determine factors associated with not testing and consistent condom use.

Results

Over two thirds (71%) of men had not had an HIV test and the majority (55%, n = 602) were young (18–23). Of those not testing, condom use was poor (44%, n = 304). Men who were 18–23 years (aOR: 2.261, CI: 1.534–3.331), with primary (aOR: 2.096, CI: 1.058–4.153) or high school (aOR: 1.622, CI: 1.078–2.439) education, had sex in the last 6 months (aOR: 1.703, CI: 1.055–2.751), and had ≥1 sexual partner (aOR: 1.749, CI: 1.196–2.557) were more likely not to test. Of those reporting condom use (n = 1036, 67%), consistent condom use was 43% (n = 451). HIV testing did not correlate with condom use.

Conclusion

Low rates of both condom use and HIV testing among men in a high HIV prevalence setting are worrisome and indicate an urgent need to develop innovative behavioral strategies to address this shortfall. Condom use is poor in this population whether tested or not tested for HIV, indicating no association between condom use and HIV testing.

The safety and efficacy of adding antiretroviral drugs to standard zidovudine prophylaxis in infants of mothers with human immunodeficiency virus (HIV) infection who did not receive antenatal antiretroviral therapy (ART) because of late identification are unclear. We evaluated three ART regimens in such infants.

Methods

Within 48 hours after their birth, we randomly assigned formula-fed infants born to women with a peripartum diagnosis of HIV type 1 (HIV-1) infection to one of three regimens: zidovudine for 6 weeks (zidovudine-alone group), zidovudine for 6 weeks plus three doses of nevirapine during the first 8 days of life (two-drug group), or zidovudine for 6 weeks plus nelfinavir and lamivudine for 2 weeks (three-drug group). The primary outcome was HIV-1 infection at 3 months in infants uninfected at birth.

Results

A total of 1684 infants were enrolled in the Americas and South Africa (566 in the zidovudine-alone group, 562 in the two-drug group, and 556 in the three-drug group). The overall rate of in utero transmission of HIV-1 on the basis of Kaplan–Meier estimates was 5.7% (93 infants), with no significant differences among the groups. Intra-partum transmission occurred in 24 infants in the zidovudine-alone group (4.8%; 95% confidence interval [CI], 3.2 to 7.1), as compared with 11 infants in the two-drug group (2.2%; 95% CI, 1.2 to 3.9; P = 0.046) and 12 in the three-drug group (2.4%; 95% CI, 1.4 to 4.3; P = 0.046). The overall transmission rate was 8.5% (140 infants), with an increased rate in the zidovudine-alone group (P = 0.03 for the comparisons with the two- and three-drug groups). On multivariate analysis, zidovudine monotherapy, a higher maternal viral load, and maternal use of illegal substances were significantly associated with transmission. The rate of neutropenia was significantly increased in the three-drug group (P<0.001 for both comparisons with the other groups).

Conclusions

In neonates whose mothers did not receive ART during pregnancy, prophylaxis with a two- or three-drug ART regimen is superior to zidovudine alone for the prevention of intrapartum HIV transmission; the two-drug regimen has less toxicity than the three-drug regimen. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development [NICHD] and others; ClinicalTrials.gov number, NCT00099359.)